EP0696210A1 - Use of hyaluronic acid and/or polydeoxyribonucleotide based hydrogels as materials for filling prostheses and prostheses obtained - Google Patents

Use of hyaluronic acid and/or polydeoxyribonucleotide based hydrogels as materials for filling prostheses and prostheses obtained

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Publication number
EP0696210A1
EP0696210A1 EP94914430A EP94914430A EP0696210A1 EP 0696210 A1 EP0696210 A1 EP 0696210A1 EP 94914430 A EP94914430 A EP 94914430A EP 94914430 A EP94914430 A EP 94914430A EP 0696210 A1 EP0696210 A1 EP 0696210A1
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EP
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Prior art keywords
hydrogel
hyaluronic acid
use according
salt
weight
Prior art date
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Granted
Application number
EP94914430A
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German (de)
French (fr)
Other versions
EP0696210B1 (en
Inventor
Jacques Le Pesteur
Gino U. Chitarrini
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LABORATOIRES SEBBIN
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LABORATOIRES SEBBIN
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/12—Mammary prostheses and implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids

Definitions

  • hydrogels based on hyaluronic acid and / or polyvinyloxyribonucleotides as filling materials for prostheses and prostheses resulting therefrom.
  • the present invention relates to the use of hydrogels based on hyaluronic acid and / or polydeoxyribonucleotides as filling materials for prostheses, in particular breast prostheses and the resulting prostheses.
  • Implanting prostheses to replace or reshape certain soft tissues is a surgical technique that has now become relatively common.
  • Such a technique is particularly used in breast surgery where there are two types of breast prostheses:
  • pre-filled consisting of a silicone elastomer bag filled with silicone gel, developed in 1962 by the Doctor
  • polyvinylpyrrolidone or PN.P manageable substance of high molecular weight.
  • the envelope when the envelope is filled with physiological saline or another liquid element, an insufficient homotheticity is obtained between the envelope and its content. Furthermore, the filling material lacks flexibility, due to the incompressible nature of the water.
  • Hyaluronic acid and its salts are products which can be used as injectables. Furthermore, hyaluronic acid gels are used in the field of surgery, in particular in ophthalmology.
  • hydrogels based on hyaluronic acid and / or polydeoxyribonucleotides in the sense therefore of the invention, is meant biocompatible hydrogels prepared:
  • natural biopolymers from natural biopolymers of hyaluronic acid and / or polydeoxyribonucleotides obtained in particular by extraction or fermentation, hereinafter called natural biopolymers
  • the particular advantage of the invention is that it offers an alternative to the conventional, but currently controversial, use of silicone gels as filling materials for prostheses.
  • This solution leads to prostheses having the same advantages in their use for replacing or reshaping soft tissues but having, moreover, the advantage of using biocompatible materials fulfilling, in particular, all the characteristics of the recommendations of standard NF EN 30993 -1 concerning the biocompatibility tests of filling products.
  • the present invention relates to the use of hydrogels based on hyaluronic acid and / or polydeoxyribonucleotides as filling materials for prostheses, in particular breast prostheses.
  • the hydrogel is a hydrogel of a salt of hyaluronic acid.
  • the hydrogel consists of a hydrogel of a polydeoxyribonucleotide.
  • the hydrogel consists of a mixture of the two types of hydrogel above.
  • Hyaluronic acid can be prepared by any known extraction or fermentation process.
  • It can be in the form of a linear or crosslinked polymer.
  • a crosslinked product is preferably used by a physical crosslinking process.
  • hyaluronic acid derivatives corresponding to a hyaluronic acid having a weight average molecular weight of between 10 ⁇ and 8.10 ⁇ daltons, preferably between 1 and 3.10 ⁇ daltons, are advantageously used. .
  • hyaluronic acid salts preferred according to the invention, mention will be made of the hyaluronic acid salts, with a cation, for example a mono- or divalent salt such as the sodium, potassium, magnesium, calcium, manganese salts.
  • a cation for example a mono- or divalent salt such as the sodium, potassium, magnesium, calcium, manganese salts.
  • Sodium salts are very particularly preferred.
  • aqueous solutions of sodium hyaluronate are used such that the capillary viscosity for aqueous solutions at 0.01% on a dry basis by weight is preferably between 2.0.10- 3 and 3.0.10 ⁇ 3 Pa.s (2.0 and 3.0 centipoise) at 30 * C.
  • the salts of hyaluronic acid are salts of hyaluronic acid and of basic natural amino acid, for example salts of hyaluronic acid and of lysine, of histidine or of arginine.
  • All the salts mentioned above can be simple or mixed salts. All of these salts can in particular be made from fermentation hyaluronic acid, the nature of the salt depending on the purification conditions used.
  • the hydrogel consists of a hydrogel of a polydeoxyribonucleotide with a weight-average molar mass of between 1.10 ⁇ and 5.10 ⁇ daltons, preferably between 3.10 ⁇ and 4.10 ⁇ daltons.
  • the polydeoxyribonucleotides are advantageously mono- or divalent salts such as the sodium, potassium, magnesium, calcium, manganese salts, advantageously the sodium salt.
  • polydeoxyribonucleotides can also be salts of polydeoxyribonucleotides with basic natural amino acids such as lysine, arginine.
  • the polydeoxyribonucleotides can be prepared by fermentation, extraction or cell culture. They are advantageously prepared by extraction from the laitance of fish, in particular salmon. Depending on the purification conditions, the various simple salts mentioned above are prepared in particular, as well as optionally mixed salts.
  • Suitable polydeoxyribonucleotides to prepare the gels of the invention are such that the capillary viscosity of their 0.1% aqueous solution on a dry basis is higher than 2.10 -3 Pa.s (2 centipoise) at 30 ° C, preferably between 2.10 -3 and 3.5.10 -3 Pa.s (2.0 and 3.5 centipoise).
  • the hydrogels which can be used are mixtures of the hydrogels of hyaluronic acid and of polydeoxyribonucleotides defined above.
  • the hydrogel is a hyaluronic acid salt hydrogel, it contains 1 to 5% by weight of hyaluronic acid salt, preferably 2 to 4%.
  • hydrogel When the hydrogel is a polydeoxyribonucleotide hydrogel it contains from 2 to 4% of polydeoxyribonucleotide.
  • the hydrogel When the hydrogel is obtained from a mixture of hyaluronic acid salt and polydeoxyribonucleotide, the proportion of polydeoxyribonucleotide is advantageously less than 50% by weight, preferably between 1 and 10%.
  • the hydrogels which can be used according to the invention are obtained from double salts of polydeoxyribonucleotides and hyaluronic acid. These salts are obtained from the salts of hyaluronic acid and of polydeoxyribonucleotides defined above.
  • the preparation of these double salts consists in bridging the chains of hyaluronic acid and the chains of deoxyribonucleic acid between them by bivalent cations, preferably calcium or magnesium.
  • the fibrous mass collected after this bridging operation is a double salt of the two finely entangled polymers.
  • the rheological characteristics of the gels obtained from the double salts are similar to those of the two starting polymers and are a function of the rates of mixing of the two polymers during the preparation.
  • the polydeoxyribonucleotides can represent up to 50% of the final product. Preferably, this rate will be between 1 and 10% by weight.
  • hydrogels When the hydrogels are formed from the above double salts, they contain a proportion of between 2 and 4% by weight of these polymers.
  • hydrogels which can be used according to the invention are prepared from the salts and mixtures defined above and from a biocompatible hydrophilic medium.
  • hydrophilic biocompatible media mention will be made of water for injections, isotonic aqueous solutions, in particular solutions containing 0.9% NaCl, buffered isotonic aqueous solutions.
  • the hydrogels are advantageously prepared in a double-jacket vacuum mixer allowing their degassing and their transfer by reduction of the viscosity.
  • hydrogels defined above can also be subjected to crosslinking intended to create bridges between the molecular chains, which leads to an increase in the viscosity of said gels.
  • This crosslinking can be either physical or chemical, the only imperative being that the products obtained are biocompatible.
  • the chemical bridges produced can be, for example, of the ether, phosphate ether, amide or sulfonate type.
  • the crosslinking can be carried out on a mixture mainly containing the natural biopolymer or derivative as it has been described previously, this biopolymer being associated with another polymer, preferably a natural polymer.
  • polymers advantageously used in combination with natural biopolymers or derivatives useful according to the invention mention will be made of hydroxymethylcellulose, collagen, chitosan, elastin.
  • the gels obtained from linear or crosslinked polymer chains are then used either to fill the envelopes intended to be used as prostheses called pre-filled prostheses, or to fill syringes intended for filling prostheses called inflatable prostheses.
  • the gels described above are used according to the invention for filling envelopes such as those currently used to form inflatable type prostheses which are therefore filled with gel after implantation in the body or of the pre-filled type. that we fill with gel before implantation.
  • the material used for the manufacture of such envelopes generally consists of silicone elastomers, mainly cold vulcanized silicone elastomer in the case of inflatable implants and hot crosslinkable silicone elastomers in the case of pre-implanted implants. -full.
  • the shape and dimensions of the envelope obviously depend on the destination of the implant.
  • any implant intended for the replacement, the substitution and the augmentation of a soft tissue can be filled with the gels described above any implant intended for the replacement, the substitution and the augmentation of a soft tissue.
  • 60 ml inflatable breast prostheses are filled with different hyaluronic acid gels, the composition of which is given in the table below.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Dermatology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Dispersion Chemistry (AREA)
  • Cardiology (AREA)
  • Materials For Medical Uses (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Use of hyaluronic acid and/or polydeoxyribonucleotide based hydrogels materials for filling prostheses, especially breast prostheses. The invention also concerns pre-filled or inflatable prostheses filled with these materials and, in particular, breast prostheses.

Description

Utilisation d'hydrogels à base d'acide hyaluronique et/ou de polvdésoxyribonucléotides comme matériaux de remplissage de prothèses et prothèses en résultant.Use of hydrogels based on hyaluronic acid and / or polyvinyloxyribonucleotides as filling materials for prostheses and prostheses resulting therefrom.
La présente invention concerne l'utilisation d'hydrogels à base d'acide hyaluronique et/ou de polydésoxyribonucléotides comme matériaux de remplissage de prothèses, en particulier de prothèses mammaires et les prothèses en résultant.The present invention relates to the use of hydrogels based on hyaluronic acid and / or polydeoxyribonucleotides as filling materials for prostheses, in particular breast prostheses and the resulting prostheses.
L'implantation de prothèses en vue de remplacer ou remodeler certains tissus mous est une technique chirurgicale maintenant devenue relativement courante.Implanting prostheses to replace or reshape certain soft tissues is a surgical technique that has now become relatively common.
Une telle technique est particulièrement utilisée dans la chirurgie des seins où il existe deux types de prothèses mammaires :Such a technique is particularly used in breast surgery where there are two types of breast prostheses:
- celles dites "pré-remplies", constituées d'une poche en élastomère de silicone remplie de gel de silicone, mises au point en 1962 par le Docteur- those called "pre-filled", consisting of a silicone elastomer bag filled with silicone gel, developed in 1962 by the Doctor
CRONIN à HOUSTON (U.S.A.).CRONIN at HOUSTON (U.S.A.).
- celles dites "gonflables", constituées d'une poche en élastomère de silicone comprenant une valve permettant l'introduction de :- those called "inflatable", consisting of a silicone elastomer pocket comprising a valve allowing the introduction of:
. sérum physiologique répondant à la pharmacopée française ayant une concentration en sel de sodium de (9 %).. physiological serum corresponding to the French pharmacopoeia having a sodium salt concentration of (9%).
. polyvinylpyrrolidone ou PN.P, substance maniable et de haut poids moléculaire.. polyvinylpyrrolidone or PN.P, manageable substance of high molecular weight.
On a également signalé récemment l'existence d'une prothèse mam¬ maire remplie d'un mélange constitué de 6 % de polysaccharides et de 94 % de sérum physiologique et mise sur le marché sous le nom d'Hydrogel par la société P.I.P.It has also recently been reported that a breast prosthesis is filled with a mixture of 6% polysaccharides and 94% physiological saline and placed on the market under the name of Hydrogel by the company P.I.P.
Il existe à l'heure actuelle une vive polémique concernant l'utilisation des prothèses remplies de gel de silicone, due à une suspicion d'éventuelle relation entre l'utilisation de gel de silicone et l'apparition de maladies auto-immunes. Par ailleurs, les autres matériaux actuellement utilisés pour le remplis¬ sage des implants ne présentent pas à l'heure actuelle tous les avantages que l'on pourrait attendre d'un matériau destiné à remplacer un tissu animal ou humain.There is currently a lively controversy concerning the use of prostheses filled with silicone gel, due to a suspicion of a possible relationship between the use of silicone gel and the appearance of autoimmune diseases. Furthermore, the other materials currently used for the filling of implants do not presently present all the advantages that one would expect from a material intended to replace animal or human tissue.
En effet, lorsque l'enveloppe est remplie de sérum physiologique ou d'un autre élément liquide, on obtient une homothéticité insuffisante entre l'enveloppe et son contenu. Par ailleurs, le matériau de remplissage manque de souplesse, du fait du caractère incompressible de l'eau. L'acide hyaluronique et ses sels sont des produits utilisables comme produits injectables. Par ailleurs, les gels d'acide hyaluronique sont utilisés dans le domaine de la chirurgie, en particulier, en ophtalmologie.Indeed, when the envelope is filled with physiological saline or another liquid element, an insufficient homotheticity is obtained between the envelope and its content. Furthermore, the filling material lacks flexibility, due to the incompressible nature of the water. Hyaluronic acid and its salts are products which can be used as injectables. Furthermore, hyaluronic acid gels are used in the field of surgery, in particular in ophthalmology.
On a signalé également plus récemment dans le Quotidien du Médecin en date du 01/03/93 l'utilisation par voie locale d'un sel d'acide hyaluronique mis au point par le Laboratoire FIDIA comme traitement symptomatique à effet prolongé de l'arthrose.It was also reported more recently in the Physician's Daily dated 03/01/93 the local use of a salt of hyaluronic acid developed by the FIDIA Laboratory as symptomatic treatment with a prolonged effect of osteoarthritis .
Par ailleurs, différents polydésoxyribonucléotides sont connus comme matières premières pharmaceutiques et utilisables également comme produits injectables et jouissent de ce fait d'une grande sécurité d'emploi.Furthermore, various polydeoxyribonucleotides are known as pharmaceutical raw materials and can also be used as injectable products and therefore enjoy great job security.
La Demanderesse a maintenant découvert que l'utilisation de gels à base d'acide hyaluronique ou de polydésoxyribonucléotides comme matériaux de remplissage de prothèses conduisait à des implants qui ne présentaient aucun des inconvénients de ceux de l'art antérieur.The Applicants have now discovered that the use of gels based on hyaluronic acid or on polydeoxyribonucleotides as filler materials for prostheses leads to implants which do not have any of the drawbacks of those of the prior art.
Par hydrogels à base d'acide hyaluronique et/ou de polydésoxyribo¬ nucléotides, au sens donc de l'invention, on entend des hydrogels biocompatibles préparés :By hydrogels based on hyaluronic acid and / or polydeoxyribonucleotides, in the sense therefore of the invention, is meant biocompatible hydrogels prepared:
- à partir des biopolymères naturels d'acide hyaluronique et/ou de polydésoxyribonucléotides obtenus notamment par extraction ou fermentation, dénommés ci-après biopolymères naturels,- from natural biopolymers of hyaluronic acid and / or polydeoxyribonucleotides obtained in particular by extraction or fermentation, hereinafter called natural biopolymers,
- à partir des biopolymères des dérivés d'acide hyaluronique et/ou de polydésoxyribonucléotides, en particulier des dérivés sous forme de sels ou d'esters, dénommés ci-après biopolymères dérivés, - par réticulation des hydrogels de biopolymères naturels et dérivés définis ci-dessus,- from biopolymers of hyaluronic acid derivatives and / or polydeoxyribonucleotides, in particular derivatives in the form of salts or esters, hereinafter called derived biopolymers, - by crosslinking of hydrogels of natural biopolymers and derivatives defined below above,
- par réticulation de mélanges contenant des biopolymères naturels et/ou dérivés définis ci-dessus et un autre polymère.- by crosslinking of mixtures containing natural biopolymers and / or derivatives defined above and another polymer.
Elle a également découvert que ces gels pouvaient être utilisés en mélange.She also discovered that these gels could be used in admixture.
Elle a également découvert que des gels intéressants comme matériaux de remplissage étaient obtenus à partir de complexes de sels d'acide hyaluronique et de polydésoxyribonucléotides.She also discovered that interesting gels as fillers were obtained from complexes of hyaluronic acid salts and polydeoxyribonucleotides.
L'avantage particulier de l'invention est qu'elle offre une solution de rechange par rapport à l'utilisation classique, mais controversée à l'heure actuelle, des gels de silicone comme matériaux de remplissage des prothèses. Cette solution conduit à des prothèses présentant les mêmes avantages dans leur utilisation pour remplacer ou remodeler des tissus mous mais présentant, en outre, l'avantage de mettre en oeuvre des matériaux biocompatibles remplissant, en particulier, toutes les caractéristiques des recommandations de la norme NF EN 30993-1 concernant les essais de biocompatibilité des produits de remplissage.The particular advantage of the invention is that it offers an alternative to the conventional, but currently controversial, use of silicone gels as filling materials for prostheses. This solution leads to prostheses having the same advantages in their use for replacing or reshaping soft tissues but having, moreover, the advantage of using biocompatible materials fulfilling, in particular, all the characteristics of the recommendations of standard NF EN 30993 -1 concerning the biocompatibility tests of filling products.
Ainsi, selon l'une de ses caractéristiques essentielles, la présente invention concerne l'utilisation d'hydrogels à base d'acide hyaluronique et/ou de polydésoxyribonucléotides comme matériaux de remplissage de prothèses, en particulier de prothèses mammaires. Selon une première variante, l'hydrogel est un hydrogel d'un sel d'acide hyaluronique.Thus, according to one of its essential characteristics, the present invention relates to the use of hydrogels based on hyaluronic acid and / or polydeoxyribonucleotides as filling materials for prostheses, in particular breast prostheses. According to a first variant, the hydrogel is a hydrogel of a salt of hyaluronic acid.
Selon une deuxième variante de l'invention, l'hydrogel est constitué d'un hydrogel d'un polydésoxyribonucléotide.According to a second variant of the invention, the hydrogel consists of a hydrogel of a polydeoxyribonucleotide.
Selon une troisième variante, l'hydrogel est constitué d'un mélange des deux types d'hydrogel ci-dessus.According to a third variant, the hydrogel consists of a mixture of the two types of hydrogel above.
L'acide hyaluronique peut être préparé par tout procédé connu d'extraction ou de fermentation.Hyaluronic acid can be prepared by any known extraction or fermentation process.
Il peut être sous forme de polymère linéaire ou réticulé.It can be in the form of a linear or crosslinked polymer.
Lorsqu'on utilise un acide hyaluronique réticulé, on utilise de préférence un produit réticulé par un procédé physique de réticulation.When a crosslinked hyaluronic acid is used, a crosslinked product is preferably used by a physical crosslinking process.
On peut également utiliser tout produit de réticulation conduisant à un hydrogel biocompatible.One can also use any crosslinking product leading to a biocompatible hydrogel.
Pour préparer les gels utilisables selon l'invention, on utilise avanta¬ geusement des dérivés d'acide hyaluronique correspondant à un acide hyaluronique présentant une masse moléculaire moyenne en poids comprise entre 10^ et 8.10^ daltons, de préférence entre 1 et 3.10^ daltons.To prepare the gels which can be used according to the invention, hyaluronic acid derivatives corresponding to a hyaluronic acid having a weight average molecular weight of between 10 ^ and 8.10 ^ daltons, preferably between 1 and 3.10 ^ daltons, are advantageously used. .
Parmi les sels d'acide hyaluronique préférés selon l'invention, on citera les sels d'acide hyaluronique, avec un cation, par exemple un sel mono- ou divalent tel que les sels de sodium, potassium, magnésium, calcium, manganèse. Les sels de sodium sont tout particulièrement préférés. On part avantageusement, pour la préparation des gels utilisables selon l'invention, de solutions aqueuses de hyaluronate de sodium telles que la viscosité capillaire pour des solutions aqueuses à 0,01 % sur sec en poids est de préférence comprise entre 2,0.10-3 et 3,0.10~3 Pa.s (2,0 et 3,0 centipoises) à 30*C. Selon une autre variante, les sels d'acide hyaluronique sont des sels d'acide hyaluronique et d'acide aminé naturel basique, par exemple des sels d'acide hyaluronique et de lysine, d'histidine ou d'arginine.Among the hyaluronic acid salts preferred according to the invention, mention will be made of the hyaluronic acid salts, with a cation, for example a mono- or divalent salt such as the sodium, potassium, magnesium, calcium, manganese salts. Sodium salts are very particularly preferred. Advantageously, for the preparation of the gels which can be used according to the invention, aqueous solutions of sodium hyaluronate are used such that the capillary viscosity for aqueous solutions at 0.01% on a dry basis by weight is preferably between 2.0.10- 3 and 3.0.10 ~ 3 Pa.s (2.0 and 3.0 centipoise) at 30 * C. According to another variant, the salts of hyaluronic acid are salts of hyaluronic acid and of basic natural amino acid, for example salts of hyaluronic acid and of lysine, of histidine or of arginine.
Tous les sels cités ci-dessus peuvent être des sels simples ou mixtes. Tous ces sels peuvent en particulier être fabriqués à partir d'acide hyaluronique de fermentation, la nature du sel dépendant des conditions de purification utilisées.All the salts mentioned above can be simple or mixed salts. All of these salts can in particular be made from fermentation hyaluronic acid, the nature of the salt depending on the purification conditions used.
Selon une autre variante de l'invention, l'hydrogel est constitué d'un hydrogel d'un polydésoxyribonucléotide de masse molaire moyenne en poids comprise entre 1.10^ et 5.10^ daltons, de préférence entre 3.10^ et 4.10^ daltons. Les polydésoxyribonucléotides sont avantageusement des sels mono- ou divalents tels que les sels de sodium, potassium, magnésium, calcium, manganèse, avantageusement le sel de sodium.According to another variant of the invention, the hydrogel consists of a hydrogel of a polydeoxyribonucleotide with a weight-average molar mass of between 1.10 ^ and 5.10 ^ daltons, preferably between 3.10 ^ and 4.10 ^ daltons. The polydeoxyribonucleotides are advantageously mono- or divalent salts such as the sodium, potassium, magnesium, calcium, manganese salts, advantageously the sodium salt.
Il peut également s'agir de sels de polydésoxyribonucléotides avec des acides aminés naturels basiques tels que la lysine, l'arginine. Les polydésoxyribonucléotides peuvent être préparés par fermentation, extraction ou culture cellulaire. Ils sont avantageusement préparés par extraction à partir de laitance de poissons, en particulier de saumon. Suivant les conditions de purification, on prépare en particulier les différents sels simples cités ci-dessus ainsi qu'éventuellement des sels mixtes. Les polydésoxyribonucléotides utilisables pour préparer les gels selon l'invention sont tels que la viscosité capillaire de leur solution aqueuse à 0,1 % sur sec est supérieure à 2.10-3 Pa.s (2 centipoises) à 30*C, de préférence comprise entre 2.10-3 et 3,5.10-3 Pa.s (2,0 et 3,5 centipoises).It can also be salts of polydeoxyribonucleotides with basic natural amino acids such as lysine, arginine. The polydeoxyribonucleotides can be prepared by fermentation, extraction or cell culture. They are advantageously prepared by extraction from the laitance of fish, in particular salmon. Depending on the purification conditions, the various simple salts mentioned above are prepared in particular, as well as optionally mixed salts. Suitable polydeoxyribonucleotides to prepare the gels of the invention are such that the capillary viscosity of their 0.1% aqueous solution on a dry basis is higher than 2.10 -3 Pa.s (2 centipoise) at 30 ° C, preferably between 2.10 -3 and 3.5.10 -3 Pa.s (2.0 and 3.5 centipoise).
Selon une autre variante de l'invention les hydrogels utilisables sont des mélanges des hydrogels d'acide hyaluronique et de polydésoxyribonucléotides définis précédemment.According to another variant of the invention, the hydrogels which can be used are mixtures of the hydrogels of hyaluronic acid and of polydeoxyribonucleotides defined above.
Lorsque l'hydrogel est un hydrogel de sel d'acide hyaluronique, il contient 1 à 5 % en poids de sel d'acide hyaluronique, de préférence 2 à 4 %.When the hydrogel is a hyaluronic acid salt hydrogel, it contains 1 to 5% by weight of hyaluronic acid salt, preferably 2 to 4%.
Lorsque l'hydrogel est un hydrogel de polydésoxyribonucléotide il contient de 2 à 4 % de polydésoxyribonucléotide.When the hydrogel is a polydeoxyribonucleotide hydrogel it contains from 2 to 4% of polydeoxyribonucleotide.
Lorsque l'hydrogel est obtenu à partir d'un mélange de sel d'acide hyaluronique et de polydésoxyribonucléotide, la proportion de polydésoxyribo¬ nucléotide est avantageusement inférieure à 50 % en poids, de préférence comprise entre 1 et 10 %. Selon une autre variante de l'invention, les hydrogels utilisables selon l'invention sont obtenus à partir de sels doubles de polydésoxyribonucléotides et d'acide hyaluronique. Ces sels sont obtenus à partir des sels d'acide hyaluronique et de polydésoxyribonucléotides définis précédemment.When the hydrogel is obtained from a mixture of hyaluronic acid salt and polydeoxyribonucleotide, the proportion of polydeoxyribonucleotide is advantageously less than 50% by weight, preferably between 1 and 10%. According to another variant of the invention, the hydrogels which can be used according to the invention are obtained from double salts of polydeoxyribonucleotides and hyaluronic acid. These salts are obtained from the salts of hyaluronic acid and of polydeoxyribonucleotides defined above.
La préparation de ces sels doubles consiste à ponter les chaînes d'acide hyaluronique et les chaînes d'acide désoxyribonucléique entre elles par des cations bivalents, de préférence du calcium ou du magnésium. La masse fibreuse recueillie après cette opération de pontage est un sel double des deux polymères finement enchevêtrés.The preparation of these double salts consists in bridging the chains of hyaluronic acid and the chains of deoxyribonucleic acid between them by bivalent cations, preferably calcium or magnesium. The fibrous mass collected after this bridging operation is a double salt of the two finely entangled polymers.
Les caractéristiques rhéologiques des gels obtenus à partir des sels doubles sont semblables à celles des deux polymères de départ et sont fonction des taux de mélange des deux polymères lors de la préparation. Les polydésoxyribo¬ nucléotides peuvent représenter jusqu'à 50 % du produit final. De préférence, ce taux sera compris entre 1 et 10 % en poids.The rheological characteristics of the gels obtained from the double salts are similar to those of the two starting polymers and are a function of the rates of mixing of the two polymers during the preparation. The polydeoxyribonucleotides can represent up to 50% of the final product. Preferably, this rate will be between 1 and 10% by weight.
L'avantage que présente ce sel double dans la fabrication d'un gel est l'utilisation d'une matière première unique parfaitement définie et dosée dont les différents constituants sont déjà intimement mélangés.The advantage of this double salt in the manufacture of a gel is the use of a single raw material, perfectly defined and dosed, the various constituents of which are already intimately mixed.
Lorsque les hydrogels sont formés à partir des sels doubles ci-dessus, ils contiennent une proportion comprise entre 2 et 4 % en poids de ces polymères.When the hydrogels are formed from the above double salts, they contain a proportion of between 2 and 4% by weight of these polymers.
Les hydrogels utilisables selon l'invention sont préparés à partir des sels et mélanges définis précédemment et d'un milieu hydrophile biocompatible. A titre de milieux hydrophiles biocompatibles, on citera l'eau pour préparation injectable, les solutions aqueuses isotoniques, en particulier des solutions à 0,9 % de NaCl, les solutions aqueuses isotoniques tamponnées.The hydrogels which can be used according to the invention are prepared from the salts and mixtures defined above and from a biocompatible hydrophilic medium. As hydrophilic biocompatible media, mention will be made of water for injections, isotonic aqueous solutions, in particular solutions containing 0.9% NaCl, buffered isotonic aqueous solutions.
Les hydrogels sont avantageusement préparés dans un mélangeur sous vide à double enveloppe permettant d'assurer leur dégazage et leur transfert par réduction de la viscosité.The hydrogels are advantageously prepared in a double-jacket vacuum mixer allowing their degassing and their transfer by reduction of the viscosity.
Les hydrogels définis précédemment peuvent être également soumis à une réticulation destinée à créer des pontages entre les chaînes moléculaires, ce qui conduit à une augmentation de la viscosité desdits gels.The hydrogels defined above can also be subjected to crosslinking intended to create bridges between the molecular chains, which leads to an increase in the viscosity of said gels.
Cette réticulation peut être soit physique, soit chimique, le seul impératif étant que les produits obtenus soient biocompatibles.This crosslinking can be either physical or chemical, the only imperative being that the products obtained are biocompatible.
Les pontages chimiques réalisés peuvent être par exemple de type éther, phosphate éther, amide ou sulfonate.The chemical bridges produced can be, for example, of the ether, phosphate ether, amide or sulfonate type.
A titre d'exemples de composés chimiques utilisables pour créer un tel pontage, on citera le sulfone de divinyle, le formaldéhyde ainsi que les composés présentant une fonction époxyde. Selon une autre variante de l'invention, la réticulation pourra être effectuée sur un mélange contenant majoritairement le biopolymère naturel ou dérivé tel qu'il a été décrit précédemment, ce biopolymère étant associé à un autre polymère, de préférence un polymère naturel. A titre d'exemple de polymères avantageusement utlisés en association avec les biopolymères naturels ou dérivés utiles selon l'invention, on citera l'hydroxyméthylcellulose, le collagène, le chitosane, l'élastine.As examples of chemical compounds which can be used to create such a bridging, mention will be made of divinyl sulfone, formaldehyde and also the compounds having an epoxide function. According to another variant of the invention, the crosslinking can be carried out on a mixture mainly containing the natural biopolymer or derivative as it has been described previously, this biopolymer being associated with another polymer, preferably a natural polymer. By way of example of polymers advantageously used in combination with natural biopolymers or derivatives useful according to the invention, mention will be made of hydroxymethylcellulose, collagen, chitosan, elastin.
Les gels obtenus à partir des chaînes polymériques linéaires ou réticulées sont ensuite utilisés soit pour remplir les enveloppes destinées à être utilisées comme prothèses dites prothèses pré-remplies, soit pour remplir des seringues destinées au remplissage des prothèses dites prothèses gonflables.The gels obtained from linear or crosslinked polymer chains are then used either to fill the envelopes intended to be used as prostheses called pre-filled prostheses, or to fill syringes intended for filling prostheses called inflatable prostheses.
Ces prothèses pré-remplies ou les seringues sont ensuite soumises à une opération de stérilisation selon l'une des méthodes décrites par la pharma¬ copée, puis conditionnées stérilement. Après stérilisation, la viscosité des gels mesurée à 37*C à l'aide d'un viscosimètre à mobile tournant (BROOKFIELD, LV-DV1, mobile n* 4) est comprise entre 10 et 300 Pa.s (10 000 et 300 000 centipoises) (v = 1,5 et 3,0 rpm), de préférence entre 50 et 200 Pa.s (50 000 et 200 000 centipoises) (v = 1,5 rpm) et entre 30 et 180 Pa.s (180000 centipoises) (v = 3 rpm). Les gels décrits précédemment sont utilisés selon l'invention pour remplir des enveloppes telles que celles utilisées à l'heure actuelle pour former des prothèses de type gonflables que l'on remplit donc du gel après implantation dans l'organisme ou de type pré-remplies que l'on remplit du gel avant implantation.These pre-filled prostheses or the syringes are then subjected to a sterilization operation according to one of the methods described by the pharmaceutical, then packaged sterile. After sterilization, the viscosity of gels measured at 37 ° C using a mobile rotary viscometer (Brookfield LV-DV1, mobile No. 4) is between 10 and 300 Pa.s (10 000 and 300 000 centipoise) (v = 1.5 and 3.0 rpm), preferably between 50 and 200 Pa.s (50,000 and 200,000 centipoise) (v = 1.5 rpm) and between 30 and 180 Pa.s (180,000 centipoise) (v = 3 rpm). The gels described above are used according to the invention for filling envelopes such as those currently used to form inflatable type prostheses which are therefore filled with gel after implantation in the body or of the pre-filled type. that we fill with gel before implantation.
Le matériau utilisé pour la fabrication de telles enveloppes est généra- lement constitué d'élastomères de silicone, principalement d'élastomère de silicone vulcanisé à froid dans le cas des implants gonflables et d'élastomères de silicone réticulables à chaud dans le cas des implants pré-remplis. La forme et les dimensions de l'enveloppe dépendent bien entendu de la destination de l'implant.The material used for the manufacture of such envelopes generally consists of silicone elastomers, mainly cold vulcanized silicone elastomer in the case of inflatable implants and hot crosslinkable silicone elastomers in the case of pre-implanted implants. -full. The shape and dimensions of the envelope obviously depend on the destination of the implant.
D'une façon générale, on pourra remplir avec les gels décrits précédemment tout implant destiné au remplacement, à la substitution et l'augmentation d'un tissu mou. A titre d'exemple de tels implants, on citera les implants destinés à la reconstruction des mollets, des testicules et plus particulièrement les implants de reconstruction ou d'augmentation dans les indications de plasties mammaires (implants mammaires). ExempleGenerally, it will be possible to fill with the gels described above any implant intended for the replacement, the substitution and the augmentation of a soft tissue. By way of example of such implants, mention will be made of implants intended for the reconstruction of the calves, of the testicles and more particularly the implants for reconstruction or augmentation in the indications of breast plasties (breast implants). Example
On remplit des prothèses mammaires gonflables de 60 ml avec différents gels d'acide hyaluronique dont la composition est donnée dans le tableau ci-dessous.60 ml inflatable breast prostheses are filled with different hyaluronic acid gels, the composition of which is given in the table below.
Acide hyaluronique (% en poids) Milieu hydrophileHyaluronic acid (% by weight) Hydrophilic medium
3 Eau3 Water
4 Eau4 Water
3 NaCl 0,9 % (en poids)3 NaCl 0.9% (by weight)
4 NaCl 0,9 % (en poids)4 NaCl 0.9% (by weight)
4 NaCl 0,9 % - MgCl20,6 % ( en poids)4 0.9% NaCl - MgCl 2 0.6% (by weight)
3 Tampon phosphate3 Phosphate buffer
Ces prothèses ont été soumises à un test de palpation par un chirurgien plasticien en comparaison avec une prothèse classique pré-remplie de gel de silicone et ont donné des résultats équivalents. These prostheses were subjected to a palpation test by a plastic surgeon in comparison with a conventional prosthesis pre-filled with silicone gel and gave equivalent results.

Claims

REVENDICATIONS
1. Utilisation d'hydrogels à base d'acide hyaluronique et/ou de poly¬ désoxyribonucléotides comme matériaux de remplissage de prothèses, en particulier de prothèses mammaires.1. Use of hydrogels based on hyaluronic acid and / or poly¬ deoxyribonucleotides as filling materials for prostheses, in particular breast prostheses.
2. Utilisation selon la revendication 1, caractérisée en ce que l'acide hyaluronique a une masse moléculaire moyenne en poids comprise entre 10° et 8.106 daltons.2. Use according to claim 1, characterized in that the hyaluronic acid has a weight average molecular weight of between 10 ° and 8.10 6 daltons.
3. Utilisation selon l'une des revendications 1 ou 2, caractérisée en ce que le polydésoxyribonucléotide a une masse moléculaire moyenne en poids comprise entre 10^ et 5.10^ daltons.3. Use according to one of claims 1 or 2, characterized in that the polydeoxyribonucleotide has a weight average molecular weight between 10 ^ and 5.10 ^ daltons.
4. Utilisation selon l'une des revendications 1 à 3, caractérisée en ce que l'hydrogel est un hydrogel d'un sel simple ou mixte, avec un cation mono- ou divalent ou avec un acide aminé naturel basique d'acide hyaluronique ou de désoxyribonucléotide4. Use according to one of claims 1 to 3, characterized in that the hydrogel is a hydrogel of a simple or mixed salt, with a mono- or divalent cation or with a basic natural amino acid of hyaluronic acid or deoxyribonucleotide
5. Utilisation selon la revendication 4, caractérisée en ce que ledit cation est le sodium, le magnésium, le potassium, le calcium, le manganèse, de préférence le sodium.5. Use according to claim 4, characterized in that said cation is sodium, magnesium, potassium, calcium, manganese, preferably sodium.
6. Utilisation selon l'une des revendications 1 à 5, caractérisée en ce que l'hydrogel est un hydrogel d'un sel d'acide hyaluronique contenant 1 à 5 % en poids de sel d'acide hyaluronique.6. Use according to one of claims 1 to 5, characterized in that the hydrogel is a hydrogel of a salt of hyaluronic acid containing 1 to 5% by weight of salt of hyaluronic acid.
7. Utilisation selon la revendication 6, caractérisée en ce que l'hydrogel contient 2 à 4 % en poids de sel d'acide hyaluronique.7. Use according to claim 6, characterized in that the hydrogel contains 2 to 4% by weight of hyaluronic acid salt.
8. Utilisation selon l'une des revendications 1 à 5, caractérisée en ce que l'hydrogel est un hydrogel de polydésoxyribonucléotide contenant 2 à 4 % en poids de polydésoxyribonucléotide.8. Use according to one of claims 1 to 5, characterized in that the hydrogel is a polydeoxyribonucleotide hydrogel containing 2 to 4% by weight of polydeoxyribonucleotide.
9. Utilisation selon l'une des revendications 1 à 5, caractérisée en ce que l'hydrogel est un mélange d'hydrogel de sel(s) d'acide hyaluronique et de sel(s) de polydésoxyribonucléotide, le(s) sel(s) de polydésoxyribonucléotide représentant au plus 50 % en poids du poids total des sel(s), de préférence 1 à 10 %.9. Use according to one of claims 1 to 5, characterized in that the hydrogel is a mixture of hydrogel of salt (s) of hyaluronic acid and salt (s) of polydeoxyribonucleotide, the salt (s) ( s) of polydeoxyribonucleotide representing at most 50% by weight of the total weight of the salt (s), preferably 1 to 10%.
10. Utilisation selon l'une des revendications 1 à 5, caractérisée en ce que l'hydrogel est un hydrogel d'un sel double d'acide hyaluronique et de polydésoxyribonucléotide.10. Use according to one of claims 1 to 5, characterized in that the hydrogel is a hydrogel of a double salt of hyaluronic acid and of polydeoxyribonucleotide.
11. Utilisation selon la revendication 10, caractérisée en ce que lesdits sels doubles sont obtenus par pontage entre les chaînes d'acide hyaluronique et d'acide polydésoxyribonucléique. 11. Use according to claim 10, characterized in that said double salts are obtained by bridging between the chains of hyaluronic acid and of polydeoxyribonucleic acid.
12. Utilisation selon l'une des revendications 10 ou 11, caractérisée en ce que ledit sel double contient jusqu'à 50 % en poids de polydésoxy¬ ribonucléotide, de préférence 1 à 10 %.12. Use according to one of claims 10 or 11, characterized in that said double salt contains up to 50% by weight of polydésoxy¬ ribonucleotide, preferably 1 to 10%.
13. Utilisation selon l'une des revendications 10 à 12, caractérisée en ce que l'hydrogel comprend 2 à 4 % en poids dudit sel double.13. Use according to one of claims 10 to 12, characterized in that the hydrogel comprises 2 to 4% by weight of said double salt.
14. Utilisation selon l'une des revendications 1 à 13, caractérisée en ce que Thydrogel est soumis à une réticulation destinée à créer des pontages entre les chaînes moléculaires.14. Use according to one of claims 1 to 13, characterized in that Thydrogel is subjected to crosslinking intended to create bridges between the molecular chains.
15. Utilisation selon l'une des revendications 14, caractérisée en ce que l'acide hyaluronique et/ou les polydésoxyribonucléotides et/ou leurs dérivés sont utilisés en mélange avec un autre polymère, de préférence un polymère naturel, ledit mélange contenant majoritairement l'acide hyaluronique et/ou les poly¬ désoxyribonucléotides et/ou leurs dérivés.15. Use according to one of claims 14, characterized in that the hyaluronic acid and / or the polydeoxyribonucleotides and / or their derivatives are used in mixture with another polymer, preferably a natural polymer, said mixture mainly containing the hyaluronic acid and / or poly¬ deoxyribonucleotides and / or their derivatives.
16. Utilisation selon l'une des revendications 1 à 15, caractérisée en ce que la phase aqueuse constituant l'hydrogel est un mélange hydrophile bio¬ compatible.16. Use according to one of claims 1 to 15, characterized in that the aqueous phase constituting the hydrogel is a hydrophilic mixture bio¬ compatible.
17. Utilisation selon l'une des revendications 1 à 16, caractérisée en ce que l'hydrogel présente une viscosité mesurée à 37*C à l'aide d'un viscosimètre à mobile tournant de type Brookfield LV-DN1, mobile n* 4, comprise entre 10 et 300 Pa.s (v = 1,5 et 3,0 rpm).17. Use according to one of claims 1 to 16, characterized in that the hydrogel has a viscosity measured at 37 * C using a viscometer with a rotary mobile of Brookfield type LV-DN1, mobile no * 4 , between 10 and 300 Pa.s (v = 1.5 and 3.0 rpm).
18. Prothèse obtenue par remplissage d'une enveloppe avec un hydrogel tel que défini dans les revendications 1 à 17. 18. Prosthesis obtained by filling an envelope with a hydrogel as defined in claims 1 to 17.
EP94914430A 1993-04-30 1994-04-21 Use of hyaluronic acid and/or polydeoxyribonucleotide based hydrogels as materials for filling prostheses and prostheses obtained Revoked EP0696210B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9305135 1993-04-30
FR9305135A FR2704431B1 (en) 1993-04-30 1993-04-30 Use of hydrogels based on hyaluronic acid and / or polydeoxyribonucleotides as filling materials for prostheses and prostheses resulting therefrom.
PCT/FR1994/000448 WO1994025078A1 (en) 1993-04-30 1994-04-21 Use of hyaluronic acid and/or polydeoxyribonucleotide based hydrogels as materials for filling prostheses and prostheses obtained

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EP0696210A1 true EP0696210A1 (en) 1996-02-14
EP0696210B1 EP0696210B1 (en) 1998-09-02

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DE (1) DE69413023D1 (en)
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WO1994025078A1 (en) 1994-11-10
DE69413023D1 (en) 1998-10-08
FR2704431A1 (en) 1994-11-04
FR2704431B1 (en) 1995-07-21

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